Newcastle University experts in hunt for "smoking gun" of chronic fatigue syndrome ME

UNIVERSITY scientists are leading research to develop a simple blood test for the chronic fatigue syndrome ME.

Researchers from Newcastle and Oxford Universities have been awarded £50,000 funding from the ME Association to spend 12 months analysing nearly 300 blood samples, looking at metabolomics – chemical clues that are left behind after changes in cells.

Finding similarities in the cells of patients diagnosed with ME could help identify a test for the condition – and ultimately a cure.

Dr Charles Shepherd, medical adviser for the ME Association, said: “Put simply, this is the hunt for a smoking gun.

“This could be a major breakthrough.

He added: “Once and for all, we would be able to dispel the myth that ME should be treated as a psychological illness which is primarily in the mind.”

I don't believe in one simple bloodtest for a heterogeneous disorder. It doesn't match with the findings.

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It might be that we have a common endpoint that is measurable in a single blood test. Even if there is nothing to find, a negative result would still be valuable. This research is definitely worth doing.

We have received almost £30,000 in donations in just two weeks - which is a pretty good response!

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Just to be clear, the research has not actually been funded yet? The reason I ask is that I assumed it had and so I emailed my immunologist at the RVI in Newcastle this morning - the regional ME 'champion' - to ask if I could be included, and he said he hadn't heard of any research taking place at Newcastle. He is a colleague of Julia Newton so I was quite surprised by that.

Just to be clear, the research has not actually been funded yet? The reason I ask is that I assumed it had and so I emailed my immunologist at the RVI in Newcastle this morning - the regional ME 'champion' - to ask if I could be included, and he said he hadn't heard of any research taking place at Newcastle. He is a colleague of Julia Newton so I was quite surprised by that.

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The research has not yet started

We are raising money to fund this research study through our Xmas Appeal

This is the MEA website information from the launch of the appeal just over two weeks ago:

Now, the interesting thing about the "ATP Profiles" blood test is that the faults it finds in the energy metabolism of ME/CFS patients are different for every patient. If you were just to measure one area of energy metabolism, you would not get the above graph that neatly distinguishes ME/CFS patients from healthy controls, because even the severe ME/CFS patients were often found to be perfectly normal in some areas of their energy metabolism operation, but highly defective in other areas. So you have to take all areas into account when distinguishing patients from healthy controls.

I mention this because when trying to find a biomarker for ME/CFS via metabolomic analysis, it is quite possible that you will not find one single biomarker that neatly distinguishes ME/CFS patients from healthy controls; you may find different ME/CFS patient subsets, and will only be able to separate ME/CFS patients from healthy controls when you take all the subsets into account.

In one ME/CFS patient subset, there may be a certain set of metabolic signatures present — call it set 1. But in a different ME/CFS patient subset, the set 1 metabolic signatures may be entirely absent, but in these patients you may instead find another set of metabolic signatures present — call it set 2. Thus if you were only testing ME/CFS patients using the set 1 signatures, you'd miss all the ME/CFS patients who have set 2 signatures.

So I think this sort of thing needs to be borne in mind when searching for metabolomic signatures present in ME/CFS patients.

We need independent replication. I've seen a number of people be critical of that 2009 paper from Myhill, Booth and McLaren-Howard. Wasn't MEA involved in some sort of replication attempt? Not sure if we have results from that yet.

@Hip - I had ATP testing done by Sarah Myhill 6-1/2 years ago and it showed marked deficiencies in ATP production. But I can't tell where I would be plotted on your graph.

She did 6 different tests, and I'm assuming the one related to your graph is the one that has 3 parts: ATP Studies on Neutrophils, ADP to ATP conversion efficiency and ADP-ATP Translocator. My results were low on every variable but don't know how they fit into your graph.

There is a number at the bottom of the page, 15/100, and I don't know what it means. There's another number at the bottom which is 0.11, and again it's not identified.

Can you tell me if either of these two numbers identify where I would fit on your graph?

Or if you needed all the variable figures (11 of them), I'd be happy to post them. Thanks for your help.

I don't believe in one simple bloodtest for a heterogeneous disorder. It doesn't match with the findings.

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Agreed. Why must the disease be obvious in blood? It could be a malfunction in x bodily process which does not leave obvious signs in blood. We're not looking for a virus, bacteria or foreign substance, though those may be present in addition to whatever knocked us out.

Let me make an anology with zero knowledge of biology, thus very rough:
Imagine you have an auto engine where the even # cylinders run rich, while the odd # run lean.
Your diagnostic tools are examining the power output (exercise test) and a chemical analysis of the used engine oil. Everything reads about normal, though a close reading shows traces of unburned fuel in the engine oil and faint signs of overheating. Still, all is still broadly within the range of usual results. Dx: "No problem found."

Then, the next time the engine approaches its full design load, the lean cylinders detonate, crack pistons and the engine from then on is crippled (it will be destroyed if running with a load is attempted).

We do. But I brought up the Myhill et al paper not to discuss it so much, but as an example of the need to identify and take into account different ME/CFS patient subsets if you want to develop test that reliably distinguishes ME/CFS patients from healthy controls.

Myhill et al would not have been able to distinguish ME/CFS patients from healthy controls if they had only focused on one area of energy metabolism; it required taking into account possible dysfunctions in several different areas. That is the point I am making, and it think it would apply to metabolomic studies as well.

@Mary Why don't you repost you above post on the Myhill paper thread, and I'll try to answer your questions there. If you can take a picture of you test results page and post it, it may help.

Dr Charles Shepherd, medical adviser for the ME Association, said: “Put simply, this is the hunt for a smoking gun.

“This could be a major breakthrough.

He added: “Once and for all, we would be able to dispel the myth that ME should be treated as a psychological illness which is primarily in the mind.”

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Without wanting to be rude about it, I'm a bit concerned this sort of thing just plays into the hands of the spin we see from Wessely and co. I don't see any good reason to to bring it up when 1) it's so much less important than getting to the truth and helping find genuinely effective treatments and 2) we know how harmful it has been for ME advocacy to be presented as being in some way 'anti-psych'.

I realise it can be hard to do these sorts of things, particularly when the media seems so drawn to this 'psych vs bio' drama, and journalists will take the bits that interest them most, but this is an area where it's really worth trying to be extra careful imo.

we know how harmful it has been for ME advocacy to be presented as being in some way 'anti-psych'.

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That is the first time I have heard anyone suggest that the ME/CFS community should not be anti-BPS!

Myself I don't think the substantial progress we have made in recent years, in making the BPS model of ME/CFS look like the farce it really is, would have occurred if the ME/CFS community were not fiercely ant-BPS.

We need independent replication. I've seen a number of people be critical of that 2009 paper from Myhill, Booth and McLaren-Howard. Wasn't MEA involved in some sort of replication attempt? Not sure if we have results from that yet.

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The MEA Ramsay Research Fund is funding, or has been funding, four separate research studies into the role of mitochondrial dysfunction in ME/CFS and how it should be assessed - including the expensive commercial test that is being referred to

The main problem here is that this expensive commercial test has not been validated by other independent researchers - which is why it is not used (and is normally dismissed) by NHS doctors who specialise in muscle and mitochondrial disease

The results from the research we have funded in Newcastle are now being analysed, along with some further laboratory work which has been done on this commercial test by two other independent researchers. The results will then be submitted for publication. Once the results have been published, the MEA will be making a further statement on this commercial test.

In our present state of knowledge, there is insufficient evidence to conclude that any of these commercial mitochondrial function test results are a reliable indicator of muscle or mitochondrial involvement or function in ME/CFS

And if mitochondrial function needs to be investigated, especially to rule out primary mitochondrial disease - which can be misdiagnosed as ME/CFS, then there are 'Gold Standard' NHS tests available (muscle biopsy, MRS etc)

I would add that I have a deep personal interest in mitochondrial dysfunction having used my own skeletal muscle in the first research studies (which took place in the 1980s) to demonstrate evidence of mitochondrial dysfunction in ME/CFS.

The first research, which I did with Professor George Radda et al at Oxford, and involved magneruc resonance spectroscopy, was published in The Lancet (abstract below).

The second, which involved electron microscopy of mitochondria from biopsy specimens, was carried out by Professor Mina Behan et al in Glasgow (abstract below).

1984 Jun 23;1(8391):1367-9.Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome. A 31P nuclear magnetic resonance study.Abstract
A patient with prolonged post-viral exhaustion and excessive fatigue (CS) was examined by 31P nuclear magnetic resonance. During exercise, muscles of the forearm demonstrated abnormally early intracellular acidosis for the exercise performed. This was out of proportion to the associated changes in high-energy phosphates. This may represent excessive lactic acid formation resulting from a disorder of metabolic regulation. The metabolic abnormality in this patient could not have been demonstrated by traditional diagnostic techniques.

Summary
We have examined the muscle biopsies of 50 patients who had postviral fatigue syndrome (PFS) for from 1 to 17 years. We found mild to severe atrophy of type II fibres in 39 biopsies, with a mild to moderate excess of lipid. On ultrastructural examination, 35 of these specimens showed branching and fusion of mitochondrial cristae. Mitochondrial degeneration was obvious in 40 of the biopsies with swelling, vacuolation, myelin figures and secondary lysosomes. These abnormalities were in obvious contrast to control biopsies, where even mild changes were rarely detected. The findings described here provide the first evidence that PFS may be due to a mitochondrial disorder precipitated by a virus infection.